Diabetes mellitus can be classified into two types: Type I (also referred to as insulin dependent diabetes mellitus) and Type II (also referred to as non-insulin dependent diabetes mellitus). Type I diabetes is an autoimmune disease wherein there is an extensive loss of the insulin producing β-cells of the pancreas. The resulting insulin deficiency leads to hyperglycemia (abnormally high glucose levels in the blood).
Type II diabetes mellitus develops as a result of non-responsiveness of muscle, fat and liver cells to insulin. This phenomenon is referred to as insulin resistance and could arise due to a reduced number of insulin receptors on the surface of these cells, or a defective insulin-mediated signaling, or a combination of both. Chronic Type II diabetes leads to pancreatic β-cell dysfunction. Surprisingly, there is no cure for diabetes. The current treatments focus on disease management, by controlling blood glucose levels and delaying complications that arise due to hyperglycemia. Treatments that target insulin resistance include metformin and TZDs (Thiazolidinediones), and those that stimulate insulin secretion, such as sulfonylureas and GLP-1 agonists. Sulfonylureas often lead to hypoglycemia due to excessive insulin secretion. Moreover, the insulin secretion, in this case, is independent of the blood glucose concentration. GLP-1 agonists stimulate insulin secretion only in the presence of glucose, but it is not orally bioavailable and has to be given intravenously. DPP-IV inhibitors work by increasing the levels of GLP-1 which in turn leads to insulin secretion. (Jones R M, et al., Expert Opin. Ther. Patents (2009) 19(10):1339-1359).
GPR119 (G protein-coupled receptor) is a member of the rhodopsin family of GPCRs and is a Gαs coupled receptor. It is expressed predominantly in the pancreas (β-cells) and gastrointestinal tract (enteroendocrine cells) in humans (Overton H A, et al., British Journal of Pharmacology (2008) 153 S76-S81). GPR119 activation by endogenous ligands (e.g., oleoylethanolamide, OEA) leads to an increase in the intracellular concentrations of cAMP, which subsequently leads to increased secretion of glucose-dependent insulinotropic peptide (GIP) and glucagon-like peptide (GLP-1). This mechanism is responsible for the glucose stimulated insulin secretion (GSIS) from the β-cells of the pancreas. Treatments that increase GLP-1 secretion may be useful for various conditions and disorders including, but not limited to, metabolic disorders, gastrointestinal disorders, inflammatory diseases, psychosomatic, depressive and neuropsychiatric diseases.
GPR119 is reported to be involved in various diseases in addition to Type 2 diabetes. These include but are not limited to obesity (Overton H A, et al., British Journal of Pharmacology (2008) 153 S76-S81) and osteoporosis (WO2007/120689 A2).
As reported in the literature, the agonists of GPR119 receptors are useful as therapeutic agents for treating or preventing a condition modulated by PYY(peptide YY), such as a condition modulated by stimulation of NPY Y2 receptor (Y2R). Conditions modulated by PYY include but are not limited to bone-related conditions, metabolic disorders, angiogenesis-related conditions, ischemia-related conditions, convulsive disorders, malabsorptive disorders, cancers, and inflammatory disorders. PCT application WO 2009/126245 A1 discloses GPR119 receptors to be involved in inflammation, inflammatory bowel disease and atherosclerosis.
Obesity is a condition in which individuals have high body mass index (BMI). Overweight conditions and obesity are closely linked to Type 2 diabetes, heart disease, increased cholesterol, dislipidemia, high blood pressure, insulin resistance, glucose intolerance, hyperinsulinemia, coronary heart disease, angina pectoris, congestive heart failure, strokes, gallstones, cholecystitis, cholelithiasis, gout, osteoarthritis, obstructive sleep apnea, respiratory problems, certain forms of cancers (endometrial, breast, prostate and colon) and psychological disorders (e.g., depression, eating disorder, low self-esteem).
Osteoporosis is characterized by the loss of bone mass and the deterioration of skeletal structure leading to decreased bone strength. Patients have an enhanced risk of fractures. Osteoporosis leads to morbidity, mortality and decreased quality of life. Osteoporotic fractures therefore cause substantial mortality, morbidity, and economic cost. With an ageing population, the number of osteoporotic fractures and their costs will at least double in the next 50 years unless effective preventive strategies are developed. (Cole et al., Curr. Rheum. Reports (2008); 10; 92-96; Reginster, Bone (2006) 38:S4-S9); Boonen, Curr. Med. Res. Opin. (2008); 24; 1781-1788).
Atherosclerosis is a condition involving inflammation, lipid accumulation, cell death (necrosis) and fibrosis. Foam cell formation results from monocyte infiltration and cholesterol deposition in the subendothelial space. Complications of atherosclerosis lead to myocardial infarction and stroke. Atherosclerosis is one of the major causes of death in many countries (Ruggeri, Nat. Med. (2002); 8; 1227-1234; Li, Nat. Med. (2002); 8; 1234-1242).
Inflammatory bowel disease (IBD) is a term that includes diseases leading to inflammation of intestine. The diseases that are classified under this category are Crohn's disease, ulcerative colitis and ulcerative proctitis.
Several patent applications disclose compounds that modulate GPR119 receptor activity and their use in the treatment of various diseases and disorders. Some of the patent applications disclosing compounds modulating GPR119 receptor activity are PCT publications JP 2011136942, WO 2010/119881, WO 2010/149685, WO 2010/128425, WO 2010/128414, WO 2010/095663, WO 2010/075271, WO 2010/075269, WO 2010/008739, WO 2009/050523, WO 2009/050522, WO 2008/054675, WO 2008/025800, WO 2007/116230, WO 2008/005576, WO 2008/005569, WO 2008/070692, WO 2007/035355, WO 2006/076243, WO 2004/065380, WO 2006/083491, WO 2006/070208, WO 2005/007647, WO 2005/121121, WO 2004/076413. Pyrimidyl indoline compounds having hypoglycemic effect are disclosed in WO 2009/051119 and WO 2009/141238.